This application seeks renewal of an ongoing grant that aims to define the genetic basis and thus the metabolic cause for the relative lack of insulin in type 2 diabetes (T2D). The proposal offers a rational strategy based on large-scale case-control genotyping of chosen genomic regions in several Caucasian populations. Among these, Ashkenazi Jews, a major focus, represent a particularly valuable population, as LD is greater and genetic heterogeneity less than in other Caucasian groups. Three specific aims are proposed. In Specific Aim 1 Ashkenazi controls (n=1000) will be collected and quantitative traits (QTs) characterized to provide adequate power for detecting low-risk alleles contributing to the T2D risk. QTs will include anthropomorphic measures and glucose tolerance testing. In Specific Aim #2, a 10Mb region on chromosome 20q where previous linkage and association with T2D was identified by this lab, will be assessed by a multi-tiered strategy including SNP genotyping in cases and controls, resequencing of positive genes, genotyping of variants discovered, and functional studies to assess the contribution of HNF4A neighboring genes as genetic markers for T2D. In-Specific Aim 3, 85 beta cell genes will be analyzed in a multi-tiered analysis similar to that of Specific Aim 2 to assess the role of these candidate genes as genetic markers for the disease. The laboratory of the principal investigator has a relatively unique combination of extensive genetic resources coupled with established experience in islet biology, providing the opportunity to explore the functional consequences of genes that appear to be risk factors as identified by genetic means. Identifying genetic markers will likely translate into better diagnosis and treatment of this disease. [unreadable] [unreadable] [unreadable]